Data have emerged implicating age-related and amyloid-induced pathology of the cerebral microvasculature as a potential contributing factor to the pathogenesis of Alzheimer's disease (AD). This project will investigate the spatial and temporal linkage between vascular pathology, amyloid and tau accumulation, and neuronal pathology.These putative interactions will be investigated in a mouse model that expresses the "Swedish" double mutation of the amyloid precursor protein (APP), and three distinct groups of human postmortem specimens: 1) neurologically normal elderly cases, 2) cases with mild cognitive impairment and early AD, and 3) centenarian brains. These analyses will focus on the hippocampus and entorhinal cortex as they are the earliest cortical regions to be involved by the degenerative process during brain aging and in AD. Specific Aim I will involve a detailed quantitative analysis of the vasculature of the hippocampus and entorhinal cortex in the three groups of human subjects. We hypothesize that a strong spatial and temporal relationship will exist between the degree of vascular damage and reflections of degeneration. We will employ stereologic probes to develop an accurate quantitative appraisal of the vasculature density in a region- and layer-specific manner. Specific Aim II will involve a comparable analysis in the cerebral cortex of Tg2576 transgenic mice expressing the "Swedish" mutation of APP. We will test the hypothesis that the APP(swe) mice show an age-related pathology of the cortical microvasculature that is similar to that found in AD in humans. Moreover, we propose that the accrued deposition of amyloid in these mice leads to severe changes in the morphologic integrity of the neurons in the vicinity of the deposits. Neuronal morphology will be assessed in a quantitative manner using intracellular injection of hippocampal and neocortical neurons with computerized reconstruction. Specific Aim III will involve ex vivo high resolution magnetic resonance microimaging at 9.4 T (MRM). These MRM data will be related to the morphologic alterations analyzed in Specific Aim II. We hypothesize that there will be an age-dependent loss of volume in hippocampal and entorhinal regions in these transgenic mice and this will correlate with the severity of vascular changes. This project will provide a quantitative assessment of the relative contribution in time and space of age-related amyloid deposition and microvascular damage to neuronal pathology in vulnerable cortical circuits critical for memory and cognition.